Mouse models of colon cancer are a critical experimental tool for determining the role of specific genes in carcinogenesis, studying tumor initiation and progression, and testing potential chemopreventive and therapeutic compounds. Typically, mouse study outcomes are determined by sacrifice and colon tissue harvesting for procedures such as tumor count, immunohistochemistry, and various assays. Since each animal can only be analyzed once, comparison across timepoints must be done statistically. With this method, it is impossible to know the progression (and possible regression) history of a lesion. We are changing the current destructive paradigm through the use of miniaturized combined reflectance and fluorescence endoscopes. Our current endoscopes contain optical coherence tomography and laser induced fluorescence to enable non-destructive, high resolution and high sensitivity imaging for time-serial visualization of an individual animal's disease. In the current funding period, we performed several studies to prove the utility of dual-modality imaging to visualize disease progression, with and without targeted fluorescence and scattering contrast agents. In this renewal, we will refine the imaging instrumentation and contrast agents based on our experience and the needs of the mouse imaging community. We will then utilize this technology for scientifically-compelling studies of carcinogenesis and chemoprevention/therapy. Our technology will enable questions regarding disease progression and regression to be answered that are difficult, if not impossible, to do with the current (sacrifice and tissue harvest) paradigm. The specific aims are: 1. Enhance the capability of the reflectance/fluorescence endoscopic systems. We will modify our endoscope to add a magnifying surface view for chromoendoscopy, to view the earliest putative lesion, aberrant crypt foci (ACF). Other system improvements include speed and automation enhancements. 2. Develop novel targeted contrast agents. We will continue to develop targeted contrast agents, focusing on the targets VEGFR and EGFR. Gold nanoparticles will be used as OCT reporters. LIF reporters will include cyanine dyes, cadmium-free nanodots, and upconverting lanthanide particles. 3. Perform chemoprevention and chemotherapeutic studies. We will perform four studies: a) How do ACF and gastrointestinal neoplasias progress to adenoma and/or adenocarcinoma? b) Can treatment with -difluoromethylornithine (DFMO) and/or sulindac regress adenoma and prevent adenocarcinoma? c) What role does the RAS oncogene play in sulindac prevention of azoxymethane-induced cancer? d) Can an alternative scheduling of sulindac provide effective chemoprevention at a lower dose? At the conclusion of this next funding period, we expect to have developed a powerful endoscopy system and to have made significant advances in the basics science of chemoprevention/chemotherapy, which can be applied to the prevention and treatment of colon cancer in humans.